To reveal the effects of candidate genes on brain function in schizophrenia, we will employ a two-stage screening process to test genes for association with context processing deficits and prefrontal cortical dysfunction. Using an endophenotype-driven approach, we will determine whether mutations in glutamatergic genes underpin neural and cognitive risk for schizophrenia. 1) The first stage will test whether five glutamate moderating genes (RGS4, DTNBP1, GRM3, NRG1, and DAOA) are associated with individual differences in context processing in a large general population sample. We will also use resampling techniques to explore whether seven less established glutamate moderating genes (GRIA2, EPSIN 4, PPP3CC, GRIN, DAO, PRODH and YWHAH) contribute to context processing, and whether glutamate polymorphisms interact with the schizophrenia risk allele of COMT. 2) The second stage will evaluate whether glutamate modulating genes associated with context processing in the general population are related to context processing deficits in schizophrenia patients and their biological relatives. 3) Finally, to understand the relationship between glutamate polymorphisms and brain dysfunction, we will use functional magnetic resonance imaging (fMRI) to examine prefrontal cortical activity in healthy relatives of schizophrenia patients and controls during performance of a context processing task. This project falls within the scope of the R21 mechanism because studies in the general population and schizophrenia are established and funded. R21 funding will support behavioral phenotyping and genotyping, but not fMRI scanning, recruitment, or additional blood sampling costs. The current study has the potential to confirm the importance of glutamate modulating genes in the etiology of schizophrenia and highlight the intermediate mechanisms through which these genes lead to disease manifestation. PUBLIC HEALTH RELEVANCE: To reveal the effects of candidate genes on brain function in schizophrenia, we will employ a two-stage screening process to test genes for association with context processing deficits and prefrontal cortical dysfunction. The first stage will test whether glutamate moderating genes are associated with individual differences in context processing in a large general population registry. The second stage will evaluate whether positively screened glutamate genes are related to context processing deficits in schizophrenia patients and their biological relatives, and determine whether these genes are related to fMRI measures of brain function in relatives and controls.